Systemic sclerosis (SSc) is a highly challenging chronic condition that is dominated by the pathogenetic triad of vascular damage, immune dysregulation/autoimmunity and fibrosis in multiple organs. A hallmark of SSc is the remarkable degree of molecular and phenotypic disease heterogeneity, which surpasses that of other complex rheumatic diseases. Disease trajectories in SSc are unpredictable and variable from patient to patient. Disease-modifying therapies for SSc are lacking, long-term morbidity is considerable and mortality remains unacceptably high. Currently-used empirical approaches to disease modification have modest and variable clinical efficacy and impact on survival, are expensive and frequently associated with unfavorable side effects, and none can be considered curative. However, research during the past several years is yielding significant advances with therapeutic potential. In particular, the application of unbiased omics-based discovery technologies to large and well-characterized SSc patient cohorts, coupled with hypothesis-testing experimental research using a variety of model systems is revealing new insights into SSc that allow formulation of a more nuanced appreciation of disease heterogeneity, and a deepening understanding of pathogenesis. Indeed, we are now presented with numerous novel and rationally-based strategies for targeted SSc therapy, several of which are currently, or expected to be shortly, undergoing clinical evaluation. In this review, we discuss promising novel therapeutic targets and rationally-based approaches to disease modification that have the potential to improve long-term outcomes in SSc.

中文翻译：

---

系统性硬化症中基于理性的治疗性疾病修饰：新策略。

系统性硬化症（SSc）是一种极富挑战性的慢性疾病，主要由多种器官的血管损伤，免疫失调/自身免疫和纤维化的致病性三联症所主导。SSc的标志是分子和表型疾病异质性的显着程度，超过了其他复杂的风湿性疾病。SSc中的疾病轨迹是不可预测的，并且因患者而异。缺乏用于SSc的疾病改良疗法，长期发病率很高，死亡率仍然高得令人无法接受。当前使用的用于疾病改良的经验方法具有适度且可变的临床功效和对生存的影响，价格昂贵并且经常与不良副作用相关，并且没有一种可以被认为是治愈性的。然而，过去几年的研究取得了巨大的进展，具有治疗潜力。尤其是，基于无偏组学的发现技术在大型且特征明确的SSc患者队列中的应用，再加上使用各种模型系统进行的假设检验实验研究，揭示了对SSc的新见解，从而使人们可以对SSc进行更细微的理解。疾病异质性，以及对发病机理的加深了解。实际上，我们现在已经获得了针对靶向SSc治疗的众多新颖且基于理性的策略，其中一些目前或预期不久将进行临床评估。在这篇综述中，我们讨论了有希望的新颖治疗靶标和基于疾病的合理治疗方法，这些方法有可能改善SSc的长期疗效。